Countering Oxidative Stress In The Retina With The Ubiquitin System
The aim of this application is to test the hypothesis that the ubiquitin system can be manipulated to augment the inherent anti-oxidant system present in retinal pigment epithelial (RPE) cells and photoreceptors. The ubiquitin system is one of the methods that cells use to destroy old or unnecessary proteins, and can be used to help regulate the activities of cellular protein. This hypothesis will be tested in mice using a virus to over-express a ubiquitin-conjugating enzyme (UbcM2) coupled to a well-established, light-stress model of retinal degeneration.
Cells in the eye that are essential for vision can be damaged or killed by different types of stress, including bright light. The loss of these cells causes a decrease in visual acuity and can ultimately cause loss of vision. These same cells have a defense system to protect themselves against stress. The main component of this defense system is a protein called Nrf2. The work of this proposal is intended to increase the function of Nrf2 and thereby help protect eyes from stress-induced damage. This will be accomplished using a protein called UbcM2. UbcM2 increases the amount of Nrf2 in cells. The specific aim of this study is to test the ability of extra UbcM2 to protect mice eyes from stress-induced damage. The idea being studied here is that by introducing extra UbcM2 into mouse eyes, Nrf2 levels will be increased. This increase in Nrf2 will defend the cells of the eye against stress-induced damage. This approach is novel and is anticipated to provide new strategies for developing drugs that can prevent the onset of age-related macular degeneration.